rs78564552

Positions:

• chr3-3175249-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000231948.9(CRBN):​c.88G>A​(p.Glu30Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00344 in 1,610,774 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (13 hom.)
• Consequence: CRBN ENST00000231948.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.16

Genes affected

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070037544).
• BP6: Variant 3-3175249-C-T is Benign according to our data. Variant chr3-3175249-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210764.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00261 (396/151976) while in subpopulation NFE AF= 0.00471 (320/67950). AF 95% confidence interval is 0.00428. There are 0 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRBN	NM_016302.4	c.88G>A	p.Glu30Lys	missense_variant	2/11	ENST00000231948.9	NP_057386.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRBN	ENST00000231948.9	c.88G>A	p.Glu30Lys	missense_variant	2/11	1	NM_016302.4	ENSP00000231948	P4

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 396 AN: 151860 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00260 AC: 653 AN: 251208 Hom.: 3 AF XY: 0.00275 AC XY: 373 AN XY: 135764

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00483

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00352 AC: 5139 AN: 1458798 Hom.: 13 Cov.: 29 AF XY: 0.00352 AC XY: 2556 AN XY: 725986

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00427

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome AF: 0.00261 AC: 396 AN: 151976 Hom.: 0 Cov.: 33 AF XY: 0.00244 AC XY: 181 AN XY: 74280

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00190

Gnomad4 NFE AF: 0.00471

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00412 Hom.: 1

Bravo AF: 0.00237

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00279 AC: 339

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00551

EpiControl AF: 0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CRBN: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.029	.;D;D
Sift4G	Benign	0.082	.;T;T
Polyphen		0.18, 0.28	.;B;B
Vest4		0.21, 0.23
MVP		0.79
MPC		0.11
ClinPred		0.050	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78564552; hg19: chr3-3216933;